Kallikreins are a large family of homologous serine proteases that act in a variety of circulatory and immune system functions (MacDonald R J et al (1988) Biochem J 253: 313-321; Murray S R et al (1990) J Cardiovasc Pharmacol 15 Suppl 6: S7-16). They may exist in blood plasma or be associated with the cell membrane. Kallikreins act both locally and systemically to regulate blood flow and pressure. They are capable of specifically cleaving low molecular weight kininogen to generate vasoactive kinin peptides, such as the potent vasodialator, bradykinin (Pisano J J (1979) Handb Exp Pharmacol 25: suppl 273-285; Schachter M (1979) Pharmacol Rev 31: 1-17). Genetic and transgenic studies have also indicated that kallikreins play a role in blood pressure regulation (Berry T D et al (1989) Hypertension 13: 3-8; Woodley-Miller et al 1989; Pravenac M et al (1991) Hypertension 17: 242-246; Wang J et al (1994) Hypertension 23: 236-243).
Kallikrein has a dual function in the blood coagulation cascade. Kallikrein can promote blood clot formation by activating factor XI, an early component of the cascade (Griffin J H et al (1976) Proc Natl Acad Sci 73: 2554-2558) and in an existing blood clot can stimulate the formation of plasmin, which will lyse the clot and destroy clotting factors (Heimark R L et al (1980) Nature 286: 456-460).
Kallikrein has important immunological functions. Plasma kallikrein can stimulate human neutrophils to aggregate and degranulate, releasing their lysosomal contents (Schapira M et al (1982) J Clin Invest 69: 1199-1202). In addition, plasma kallikrein incubated with the complement component C5 generates immunologically active fragments of C5 (Wiggins R C et al (1981) J Exp Med 153: 1391-1404). Several investigators have found evidence for a kallikrein role in the inflammatory response. In one study, Clements J A et al (1995, Endocrinology 136: 1137-1144) reported tissue kallikrein expression and activity in the periovalatory period in the gonadotropin-primed immature female ovary suggesting a role in the inflammatory-like response at ovulation.
The greatest nucleotide differences among the kallikreins are in the 5' end of the mRNA. The regulation of the mRNA stability and/or turnover rate of kallikrein may be affected by its 5' end in a species-dependent manner (Seidah N G et al (1990) DNA Cell Biol 9: 737-748). In addition, researchers speculate that small sequence differences among kallikrein genes play a role in generating diverse patterns of tissue-specific expression and function (Wines D R et al (1991) J Mol Evol 32: 476-492).
A local kallikrein-kinin system is present in rat hearts (Nolly N et al (1994) Hypertension 23: 919-923). Evidence was found for kallikrein activity and gene expression in rat heart tissues. Kinins mediate part of the beneficial cardiac effects induced by treatment with angiotensin-converting enzyme inhibitors in ischemia-reperfusion injury, myocardial infarction, and cardiac hypertrophy. Researchers did not determine whether the rat heart kallikrein-kinin system acts independently of the kallikrein-kinin systems of other tissues or blood plasma.
Kallikreins and Disease
Cardiopulmonary bypass can cause severe hemorrhagic complications by initiating a biochemical and cellular inflammatory response. It has been suggested that selective inhibitors of kallikrein may be effective in the attenuation of the contact-mediated inflammatory response in cardiopulmonary bypass (Wachtfogel Y T et al (1995) Am J Physiol 268: H1352-1357).
The selective tissue kallikrein inhibitor CH-694 caused highly significant decrease in kallikrein activity and in airway resistance when administered intraperitoneally before or after challenge in ovalbumin-sensitized guinea pigs (Szelke M et al (1994) Braz J Med Biol Res 27: 1943-1947). Thus, inhibitors of tissue kallikrein may prove effective in the treatment of allergic inflammation.
Specific kallikrein inhibitors decrease joint swelling and anemia in a rat model for arthritis, perhaps by interfering with kallikrein induced inflammatory reactions (Dela Cadena R A et al (1995) FASEB J 9: 446-452). Thus, specific kallikrein inhibitors may have therapeutic potential for arthritis patients.
The potential for using kallikrein gene therapy for the treatment of high blood pressure was investigated in rats. Human kallikrein gene delivered intravenously to spontaneously hypertensive rats caused a significant and sustained reduction in systemic blood pressure (Wang C et al (1995) J Clin Invest 95: 1710-1716). Therefore, kallikrein gene therapy may one day become a treatment option for the approximately 25% of the population afflicted with hypertension.
Angiotensin-converting enzyme inhibitors (ACEi) are widely used in the treatment of hypertension and heart failure. Evidence suggests that kinins mediate some of the effects of ACEi in treatments for ischemia-reperfusion injury, myocardial infarction, and cardiac hypertrophy (Nolly et al, supra). Involvement of kinins in the cardiac effects of ACEi suggests the presence of an independent cardiac kallikrein-kinin system. Whereas, 14 kallikrein gene family members have been characterized in mice, only 3 have been discovered to date in humans, none of which are localized to the heart (Wines et al, supra). Discovery of a kallikrein active in the heart is very desirable, as it provides the possibility of new treatments for hypertension, heart failure, inflammation, and blood clotting disorders.